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1.
Immunity ; 52(1): 151-166.e6, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31924474

RESUMO

In addition to helper and regulatory potential, CD4+ T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4+ T cells following immunotherapy. CD4+ transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4+, and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-γ (IFN-γ) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4+ T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4+ T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation.


Assuntos
Granzimas/imunologia , Neoplasias/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Transferência Adotiva , Animais , Linhagem Celular Tumoral , Humanos , Interferon gama/imunologia , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/citologia , Microambiente Tumoral/imunologia
2.
Chem Pharm Bull (Tokyo) ; 68(1): 91-95, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902904

RESUMO

Magnolia Flower is a crude drug used for the treatment of headaches, toothaches, and nasal congestion. Here, we focused on Magnolia kobus, one of the botanical origins of Magnolia Flower, and collected the flower parts at different growth stages to compare chemical compositions and investigate potential inhibitory activities against interleukin-2 (IL-2) production in murine splenic T cells. After determining the structures, we examined the inhibitory effects of the constituents of the bud, the medicinal part of the crude drug, against IL-2 production. We first extracted the flower parts of M. kobus from the bud to fallen bloom stages and analysed the chemical compositions to identify the constituents characteristic to the buds. We found that the inhibitory activity of the buds against IL-2 production was more potent than that of the blooms. We isolated two known compounds, tiliroside (1) and syringin (2), characteristic to the buds from the methanol (MeOH) extract of Magnolia Flower. Moreover, we examined the inhibitory activities of both compounds against IL-2 production and found that tiliroside (1) but not syringin (2), showed strong inhibitory activity against IL-2 production and inhibited its mRNA expression. Thus, our strategy to examine the relationship between chemical compositions and biological activities during plant maturation could not only contribute to the scientific evaluation of medicinal parts of crude drugs but also assist in identifying biologically active constituents that have not yet been reported.


Assuntos
Interleucina-2/metabolismo , Magnolia/química , Extratos Vegetais/química , Animais , Linhagem Celular , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Flores/química , Flores/metabolismo , Glucosídeos/química , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Interleucina-2/genética , Magnolia/metabolismo , Camundongos , Fenilpropionatos/química , Fenilpropionatos/isolamento & purificação , Fenilpropionatos/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
3.
Immunity ; 51(6): 1102-1118.e7, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31757673

RESUMO

Young children are more susceptible to developing allergic asthma than adults. As neural innervation of the peripheral tissue continues to develop after birth, neurons may modulate tissue inflammation in an age-related manner. Here we showed that sympathetic nerves underwent a dopaminergic-to-adrenergic transition during post-natal development of the lung in mice and humans. Dopamine signaled through a specific dopamine receptor (DRD4) to promote T helper 2 (Th2) cell differentiation. The dopamine-DRD4 pathway acted synergistically with the cytokine IL-4 by upregulating IL-2-STAT5 signaling and reducing inhibitory histone trimethylation at Th2 gene loci. In murine models of allergen exposure, the dopamine-DRD4 pathway augmented Th2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. Taken together, the communication between dopaminergic nerves and CD4+ T cells provides an age-related mechanism underlying the susceptibility to allergic inflammation in the early lung.


Assuntos
Neurônios Adrenérgicos/citologia , Asma/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Pulmão/patologia , Células Th2/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Asma/imunologia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-2/metabolismo , Interleucina-4/imunologia , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neurogênese/fisiologia , Receptores de Dopamina D4/metabolismo , Fator de Transcrição STAT5/metabolismo , Sistema Nervoso Simpático/citologia
4.
Cell Biochem Funct ; 37(8): 618-624, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31710117

RESUMO

The aim of this study was to investigate the effect of vaccinia virus expressing IL-37 (VV-IL-37) on cell proliferation, migration and invasion of hepatocellular carcinoma (HCC) and its possible underlying molecular mechanisms. In this study, we constructed a cancer-targeted vaccinia virus carrying the IL-37 gene knocked in the region of the viral thymidine kinase (TK) gene. Human HCC cell lines were assayed in vitro for cell proliferation, migration and invasion. Serum level, relative mRNA level and protein level of IL-37 in HCC cell lines SMMC7721 and Bel7402 were tested by ELISA assay, qRT-PCR and western blot, respectively. The levels of IL-2, IFN-γ and TNF-α in HCC tumor tissues were also analyzed by ELISA. STAT3 and p-STAT3 expression in tumor tissues were determined by western blot. Our results showed that VV-IL-37 efficiently infected and inhibited HCC cells proliferation, migration and invasion via decreasing STAT3 phosphorylation. In vivo, VV-IL-37 expressed IL-37 at a high level in the transplanted tumor, reduced STAT3 activity, and eventually inhibited tumor growth. In conclusion, we demonstrate that VV-IL-37 promotes antitumor immune responses in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Interleucina-1/metabolismo , Neoplasias Hepáticas/patologia , Vírus Vaccinia/fisiologia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-1/genética , Interleucina-2/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transplante Heterólogo , Vírus Vaccinia/genética
5.
Bioelectromagnetics ; 40(8): 588-601, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31663626

RESUMO

Owing to the development of information technology and the electronics industry, and the increase in the use of electronic products, an increasing number of people are exposed to electromagnetic fields (EMFs) in daily life. There has been concern about the effects of EMFs on the human body. Th9 cells, which are characterized by the generation of interleukin-(IL-9), are a recently defined subset of T helper (Th) cells. In this study, we investigated the effect of extremely low-frequency (60 Hz) EMFs, such as those generated by household power sources, at 0.8 mT intensity on CD4+ T cells. The exposure of CD4+ T cells to such EMFs under Th9-polarizing conditions increased IL-9 secretion and gene expression of transcription factors that are important for Th9 development. The expression of GATA3 increased in the early stage, and the phosphorylation of STAT5 and STAT6, which regulate the expression of GATA3, increased. In addition, EMFs increased the expression of IL-2 by the T cells. In conclusion, the differentiation of CD4+ T cells to the Th9 phenotype was increased by exposure to extremely low-frequency EMFs, and this appeared to be dependent on the IL-2 signaling pathway. Furthermore, co-cultures of EMF-exposed Th9 cells and mast cells showed an increased expression of mast cell proteases, FcεR1α, and mast cell-derived inflammatory cytokines compared with co-cultures of non-EMF-exposed Th9 cells and mast cells. Our results suggest that EMFs enhance the differentiation of CD4+ T cells to the Th9 phenotype, resulting in mast cell activation and inflammation. Bioelectromagnetics. 2019;40:588-601. © 2019 Bioelectromagnetics Society.


Assuntos
Diferenciação Celular , Campos Eletromagnéticos , Interleucina-2/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Linhagem Celular , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais
6.
Anticancer Res ; 39(9): 4933-4940, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519598

RESUMO

BACKGROUND: Interleukin 2 (IL2) is a significant factor activating T-cell-mediated immune response by stimulation of natural killer cells, T-cells and in development of regulatory T (Treg) cells. Recent studies have that IL2 participates in cancer development by modifying the local immune response. Based on the suggested role of the single nucleotide polymorphisms (SNPs) rs2069762, rs6822844 and rs11938795 of IL2 in the pathogenesis of certain diseases, the relationship of these SNPs with clinicopathological variables and their possible implication for prognosis and disease outcome were evaluated in a cohort of Swedish patients with colorectal cancer (CRC). MATERIALS AND METHODS: TaqMan SNP genotype assays based on polymerase chain reaction were used for analysis of the IL2 SNPs in 467 patients with CRC and 467 healthy controls. Expression analysis of IL2 in plasma and CRC tissue was also performed. RESULTS: The allelic variants T in rs11938795 and G in rs6822844 were significantly associated with a higher risk of CRC. Kaplan-Meier analysis showed that cancer-specific survival was worse for individuals with C allele for rs2069762 with stage II CRC and with T allele for rs6822844 with stage III CRC. CONCLUSION: SNPs rs2069762, rs6822844 and rs11938795 of the IL2 gene may be helpful as prognostic biomarkers in the follow-up and management of the patients.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Variação Genética , Interleucina-2/genética , Adulto , Idoso , Alelos , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imunomodulação , Interleucina-2/sangue , Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Medição de Risco
7.
Exp Parasitol ; 206: 107767, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520603

RESUMO

Schistosoma mansoni eggs can influence immune responses directed at them, and the mechanisms by which this is achieved are being unravelled. Going towards, developing effective tools for the study of how S. mansoni influences naïve T cells, we have developed S. mansoni eggs expressing chicken ovalbumin (OVA), using a lentiviral transduction system. Indeed, such a parasite could be used in conjunction with cells from OT-II transgenic mice as a source of naïve, antigen-specific T cells. The expression of the transgenic protein was confirmed by real-time RT-PCR of OVA-specific mRNA and western blotting using polyclonal antibodies specific for OVA. T cells from OT-II transgenic mice expressing a T cell receptor specific for the OVA323-339 peptide recognised the OVA-transduced S. mansoni eggs. Using flow cytometry on CFSE-labelled OT-II splenocytes, we demonstrated that OVA-transduced eggs elicit higher OT-II proliferative responses than untransduced eggs. The OT-II T cells also produced TNF-α and IFN-γ following exposure to OVA-transduced eggs. In addition, moderate amounts of IL-6 and IL-17A were also detected. In contrast, no IL-10, IL-4 and IL-2 were detected in cultures, whether the cells were stimulated with transduced or untransduced eggs. Thus, the cytokine signatures showed the transfected eggs induced predominantly a Th1 response, with a small amount of IL-6 and IL-17.


Assuntos
Ovalbumina/análise , Receptores de Antígenos de Linfócitos T/imunologia , Schistosoma mansoni/metabolismo , Linfócitos T/imunologia , Animais , Western Blotting , Galinhas , Citocinas/análise , Citocinas/metabolismo , Eletroforese em Gel de Ágar , Feminino , Citometria de Fluxo , Interleucina-17/análise , Interleucina-17/metabolismo , Interleucina-2/análise , Interleucina-2/metabolismo , Interleucina-6/análise , Interleucina-6/metabolismo , Fígado/parasitologia , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Ovalbumina/genética , Ovalbumina/imunologia , Ovalbumina/metabolismo , Óvulo/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/genética , Transcrição Reversa , Schistosoma mansoni/genética , Schistosoma mansoni/crescimento & desenvolvimento , Baço/citologia , Linfócitos T/citologia
8.
BMC Womens Health ; 19(1): 109, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405377

RESUMO

BACKGROUND: This study aims to investigate the difference in vaginal microecology, local immunity and HPV infection among childbearing-age women with different degrees of cervical lesions. METHODS: A total of 432 patients were included in this study. Among these patients, 136 patients had LSIL, 263 patients had HSIL and 33 patients had CSCC. These patients were assigned as the research groups. In addition, 100 healthy females were enrolled and assigned as the control group. RESULTS: The microbiological indexes of vaginal secretions were evaluated. Furthermore, the concentrations of SIgA, IgG, IL-2 and IL-10 in vaginal lavage fluid, as well as the presence of HPV, mycoplasma and Chlamydia in cervical secretions, were detected. The results is that: (1) Differences in evaluation indexes of vaginal microecology among all research groups and the control group were statistically significant (P < 0.0001). As the degree of cervical lesions increased, the number of Lactobacillus decreased, and there was an increase in prevalence of bacterial imbalance, and the diversity, density and normal proportion of bacteria was reduced. Furthermore, the incidence of HPV, trichomonads, clue cell and Chlamydia infection increased. Moreover, the positive rate of H2O2 decreased, while the positive rates of SNa and GADP increased. (2) Differences in the ratio of IL-2 and IL-10 in the female genital tract among all research groups and the control group were statistically significant (P < 0.0001). CONCLUSIONS: As the degree of cervical lesions increased, IL-2 decreased, IL-10 increased and IL-2/IL-10 decreased, while SIgA and IgG were elevated. The reduction of dominant Lactobacillus in the vagina, impairment of H2O2 function, flora ratio imbalance, pathogen infections, reduction in IL-2/IL-10 ratio, and changes in SIgA and IgG levels could all be potential factors that influenced the pathogenicity of HPV infection and the occurrence and development of cervical lesions.


Assuntos
Infecções por Chlamydia/epidemiologia , Infecções por Papillomavirus/epidemiologia , Lesões Intraepiteliais Escamosas Cervicais/epidemiologia , Vagina/imunologia , Vagina/microbiologia , Adulto , Líquidos Corporais/metabolismo , China/epidemiologia , Chlamydia trachomatis/isolamento & purificação , Coagulase/metabolismo , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Mycoplasma/isolamento & purificação , Neuraminidase/metabolismo , Papillomaviridae/isolamento & purificação , Esfregaço Vaginal , Adulto Jovem
9.
J Med Food ; 22(9): 937-943, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31448992

RESUMO

Polysaccharide of Atractylodes macrocephala Koidz (PAMK) has been reported to have beneficial effects on regulation of immune responses in mammals and poultry. Nonetheless, the immunoregulatory mechanism of action of PAMK remains unclear. The Toll-like receptor 4 (TLR4) signaling cascade has been proved as a classic polysaccharide-regulated pathway. The aim of this study was to explore the effects of PAMK on the TLR4 signaling pathway in the regulation of spleen function in mice. Ninety-six 5-week-old BALB/c female mice were randomly allocated into four groups with three replicates per group and eight mice per replicate in a single-factor completely randomized experimental design. The control group was fed a basic diet (PAMK free); the other three groups were fed 100, 200, or 400 mg/kg PAMK for 28 days. The spleen index, concentrations of cytokines, and mRNA and protein expression levels of genes related to TLR4 signaling were determined in spleen tissue. Compared with the control group, the spleen index significantly increased in all treatment groups. Concentrations of interleukin 2 (IL-2), IL-4, interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) in the medium-PAMK group also increased significantly. PAMK in the medium-PAMK group significantly increased both mRNA and protein expression of TLR4, myeloid differentiation factor 88 (MyD88), TNFR-associated factor 6 (TRAF6), TRAF3, and nuclear factor kappa B (NF-κB) in the spleen. In conclusion, PAMK may increase immune-response capacity of the spleen in mice via TLR4-MyD88-NF-κB signaling.


Assuntos
Atractylodes/química , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Polissacarídeos/administração & dosagem , Baço/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Feminino , Interleucina-2/genética , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Baço/metabolismo , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
PLoS Pathog ; 15(8): e1007989, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31412088

RESUMO

Defining the most penetrating correlates of protective memory T cells is key for designing improved vaccines and T cell therapies. Here, we evaluate how interleukin (IL-2) production by memory CD4 T cells, a widely held indicator of their protective potential, impacts immune responses against murine influenza A virus (IAV). Unexpectedly, we show that IL-2-deficient memory CD4 T cells are more effective on a per cell basis at combating IAV than wild-type memory cells that produce IL-2. Improved outcomes orchestrated by IL-2-deficient cells include reduced weight loss and improved respiratory function that correlate with reduced levels of a broad array of inflammatory factors in the infected lung. Blocking CD70-CD27 signals to reduce CD4 T cell IL-2 production tempers the inflammation induced by wild-type memory CD4 T cells and improves the outcome of IAV infection in vaccinated mice. Finally, we show that IL-2 administration drives rapid and extremely potent lung inflammation involving NK cells, which can synergize with sublethal IAV infection to promote acute death. These results suggest that IL-2 production is not necessarily an indicator of protective CD4 T cells, and that the lung environment is particularly sensitive to IL-2-induced inflammation during viral infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica/imunologia , Vírus da Influenza A/imunologia , Interleucina-2/metabolismo , Infecções por Orthomyxoviridae/imunologia , Pneumonia/imunologia , Animais , Feminino , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Pneumonia/metabolismo , Pneumonia/virologia
11.
Vet Immunol Immunopathol ; 216: 109892, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446206

RESUMO

Cyclosporine and glucocorticoids are powerful immunosuppressive agents used to treat many inflammatory diseases in dogs. Cyclosporine inhibits calcineurin-dependent pathways of T cell activation and resultant T cell cytokine production, and glucocorticoids directly inhibit genes coding for cytokines. Little work has been done comparing the effects of these agents on T cell cytokine production in dogs. Our study measured T cell interleukin-2 (IL-2) and interferon-gamma (IFN-γ) production using flow cytometry and T cell IL-2 and IFN-γ gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in activated canine T cells incubated with cyclosporine and dexamethasone in vitro. For flow cytometric assays, diluted whole blood was cultured for 7 h in the presence of cyclosporine (10, 100, 500, and 1000 ng/mL) or dexamethasone (10 ng/mL, 100 ng/mL, 1 µg/mL, and 10 µg/mL). For qRT-PCR, whole blood was cultured for 5 h with the same drugs at the same concentrations, and RNA was then extracted from leukocytes. Flow cytometry and qRT-PCR both demonstrated inhibition of IL-2 and IFN-γ that was concentration-dependent in response to cyclosporine, and was more variable for dexamethasone. Quantitative RT-PCR but not flow cytometry documented significant reduction of IL-2 expression after dexamethasone treatment, while both methods showed concentration-dependent suppression of IFN-γ. Quantitative RT-PCR also revealed additional cytokine suppression at higher cyclosporine concentrations, an effect not found using flow cytometry, and may therefore be the preferred method for cytokine determination in dogs. Suppression of IL-2 and IFN-γ in activated T cells may have potential as an indicator of the efficacy of cyclosporine and glucocorticoids in suppressing canine T cell function in vivo, and may therefore be of value for characterizing the immunosuppression induced by these drugs in clinical patients.


Assuntos
Ciclosporina/farmacologia , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Linfócitos T/efeitos dos fármacos , Animais , Ciclosporina/administração & dosagem , Dexametasona/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Glucocorticoides/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Interferon gama/genética , Interleucina-2/genética
12.
Pathologica ; 111(2): 62-66, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31388197

RESUMO

Introduction: There is a need for the development of new biomarkers for diagnosis and prognosis of ovarian cancer, which can ideally serve as targets for new therapeutic modalities and individualization of treatment. The objectives of this study were to determine the prognostic significance of the neutrophil/lymphocyte ratio in the peripheral blood of patients with ovarian cancer and tumor staging, and to associate this marker with the immune expression of a panel of cytokines. Methods: The study included 24 patients with malignant ovarian neoplasia treated at the Pelvic Mass Outpatient Clinic of the Clinical Hospital of the Federal University of Triângulo Mineiro. The neutrophil/lymphocyte ratio was calculated as the absolute number of neutrophils divided by the absolute number of lymphocytes. Expression of the cytokines was evaluated by the immunohistochemistry method (IL2, IL5, IL6, IL8, IL10 and TNF-R1). Fisher's statistical test was used for the comparisons of immunohistochemical expression with the neutrophil/lymphocyte ratio, and the unpaired T-Test was used in the analysis of the association of this ratio with tumor staging. Results: A neutrophil/lymphocyte ratio > 2.6 was significantly higher in the more advanced stages (II-IV) of malignant ovarian neoplasia (p = 0.0098). In addition, this ratio > 2.6 was associated with IL2 stromal immunostaining (1-3) (p = 0.0472). Conclusion: Stromal IL-2 is associated with higher a neutrophil/lymphocyte ratio, suggesting a worse prognosis in ovarian cancer and its role in tumor immunology; a neutrophil/lymphocyte ratio > 2.6 is associated with more advanced stages of malignant ovarian neoplasia.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Interleucina-2/metabolismo , Linfócitos/metabolismo , Neutrófilos/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Carcinoma Epitelial do Ovário/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Estudos Prospectivos , Células Estromais/metabolismo , Células Estromais/patologia
13.
Int J Biol Macromol ; 138: 70-78, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306705

RESUMO

Avian Leukosis Virus Subgroup J (ALV-J) is an oncogenic retrovirus, mainly spread by vertical and horizontal transmission, which have caused severe losses in world poultry industry. Sargassum fusiforme polysaccharide (SFP), a marine algae sulfated polysaccharide, has attracted more attention due to its variously biological activities. In this study, the anti-ALV-J property of SFP was assessed in vivo and in vitro. The results demonstrated that different Mw of SFPs showed virustatic activity to ALV-J in vitro by combining with the virus when ALV-J adsorbed onto the host cells. When treated with SFPs, the ALV-J gene and protein expression reduced clearly and SFP-3 (Molecular weight 9 kDa) had the best antiviral effect. Results in vivo showed that the immunosuppression of the ALV-J infected chickens were relieved by SFP-3. Moreover, SFP-3 obviously inhibit the viral shedding and alleviated the organs damage caused by ALV-J. This study offered a new method for ALV-J treatment and enriched the potential application of SFP.


Assuntos
Antivirais/farmacologia , Vírus da Leucose Aviária/efeitos dos fármacos , Polissacarídeos/farmacologia , Sargassum/química , Animais , Antígenos Virais/metabolismo , Vírus da Leucose Aviária/genética , Vírus da Leucose Aviária/imunologia , Vírus da Leucose Aviária/fisiologia , Peso Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular , Galinhas , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Masculino , Eliminação de Partículas Virais/efeitos dos fármacos
14.
Gene ; 712: 143959, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278964

RESUMO

Blockade of Hedgehog signaling can prevent osteoarthritis (OA) syndromes. However, the amelioration of related inflammation condition is limited. The purpose of this study was to observe the effect of combined use of Hedgehog signaling inhibitor GANT-61 and common clinical anti-inflammatory drug indomethacin on cartilage injury and inflammation in experimental OA mice. We found that GANT-61 and indomethacin synergistically attenuate cartilage damage and serum levels of inflammatory cytokines TNF-α, IL-2 and IL-6 in OA mice. Moreover, in vitro treatment of GANT-61 and indomethacin synergistically reduced the mRNA expression of TNF-α, IL-2 and IL-6 in lipopolysaccharide (LPS)-stimulated C28/I2 chondrocytes. Mechasnistic studies showed that GANT-61 and indomethacin synergistically attenuate the expressions of cell pyroptosis-related genes caspase-1, IL-1ß and IL-18 at mRNA and protein level. To conclude, our study showed that GANT-61 and indomethacin had a synergistically ameliorating effect on osteoarthritis by mediating chondrocytes pyroptosis.


Assuntos
Cartilagem/efeitos dos fármacos , Condrócitos/citologia , Proteínas Hedgehog/antagonistas & inibidores , Indometacina/farmacologia , Osteoartrite/tratamento farmacológico , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Cartilagem/patologia , Caspase 1/metabolismo , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piroptose , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
15.
Med Sci Monit ; 25: 4716-4722, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31281179

RESUMO

BACKGROUND A growing body of evidence suggests that systemic lupus erythematosus (SLE) may result in reversible cognitive dysfunction. Vitamin D is considered important for neurons. The therapeutic effect of vitamin D was evaluated in a rat model of SLE. MATERIAL AND METHODS There were 20 male MRL/lpr mice randomly divided into the SLE model group and the vitamin D group, in addition, 10 male C57BL 6J mice were used as the control (CON) group. Vitamin D was administered intraperitoneally (2 µg/kg) for 4 weeks. After 4 weeks of continuing intervention, we tested the cognitive function using the Morris water maze. The expression of vitamin D receptor (VDR), amyloid-ß, caspase-3, and Bcl-2 were detected by western blot analysis. RESULTS In the present study, we observed that vitamin D treatment alleviated neurobehavioral deficits in the mice with SLE. At the molecular levels, administration of vitamin D activated the expression of VDR and reduced the number of dead cells in the CA1 region of the hippocampus as well as regulated caspase-3 and Bcl-2 expression. CONCLUSIONS In conclusion, our results indicated that vitamin D played a protective role by suppressing inflammatory cytokines, thereby ultimately inhibiting the progression of apoptosis in a mouse model of SLE. Vitamin D may be promising as a protective intervention in SLE with cognitive dysfunction, and more and more experiments are warranted for its clinical testing in the near future.


Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Vitamina D/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Caspase 3/metabolismo , Citocinas/metabolismo , Hipocampo/patologia , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-2/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fatores de Tempo , Vitamina D/farmacologia
16.
Food Chem Toxicol ; 131: 110537, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150782

RESUMO

Programmed death ligand-1 (PD-L1) is an important immune checkpoint for cancer immunotherapy in clinic. In this study, we reported that platycodin D, a natural product isolated from an edible and medicinal plant Platycodon grandiflorus (Jacq.) A. DC., down-regulated the protein level of PD-L1 in lung cancer cells. Flow cytometry and immunofluorescence assay showed a weaker surface PD-L1 signal in NCI-H1975 cells after the incubation with platycodin D (10 µM) for 15 min compared to the control group. Jurkat T cells showed enhancive interleukin-2 secretion when co-cultured with platycodin D-treated NCI-H1975 cells, suggesting that platycodin D-induced PD-L1 reduction increases the activation of Jurkat T cells. An augmentation of PD-L1 protein was detected in the cell culture medium from platycodin D treatment group. Chlorpromazine (60 µM) almost abolished the platycodin D-mediated PD-L1 extracellular release and restored the membrane PD-L1. Finally, hemolysis assay exhibited that platycodin D-triggered PD-L1 extracellular release was independent of the hemolytic mechanism. Taken together, our study demonstrates that platycodin D reduces the protein level of PD-L1 in lung cancer cells via triggering its release into the cell culture medium, which sheds new light for the application of natural products in cancer immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Linhagem Celular Tumoral , Clorpromazina/farmacologia , Humanos , Interleucina-2/metabolismo , Células Jurkat , Transporte Proteico/efeitos dos fármacos
17.
Food Funct ; 10(7): 3868-3879, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31184641

RESUMO

Lycopene (LYC) has been reported to exhibit antioxidant and immunoprotective activities, and our previous studies confirmed that LYC can alleviate multiple tissue damage induced by aflatoxin B1 (AFB1). However, it is unclear whether LYC could relieve the AFB1-induced immunosuppression. Thus, forty-eight male mice were randomly allocated and treated with LYC (5 mg kg-1) and/or AFB1 (0.75 mg kg-1) by intragastric administration for 30 days. We found that LYC alleviated AFB1-induced immunosuppression by relieving splenic structure injury and increasing the spleen weight, spleen coefficient, T lymphocyte subsets, the contents of IL-2, IFN-γ and TNF-α in serum, as well as the mRNA expression of IL-2, IFN-γ and TNF-α in spleen. Furthermore, LYC inhibited oxidative stress induced by AFB1via decreasing the levels of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and malondialdehyde (MDA), while enhancing the total antioxidant capacity (T-AOC) and antioxidant enzyme activities. In addition, LYC also restrained splenic apoptosis through blocking mitochondria-mediated apoptosis in AFB1 intoxicated mice, presenting as the increase of mitochondrial membrane potential, and the decrease of cytoplasmic Cyt-c protein expression, cleaved Caspase-3 protein expression, Caspase-3/9 activities and mRNA expressions, as well as balancing the mitochondrial protein and mRNA expressions of Bax and Bcl-2. These results indicate that LYC can alleviate AFB1-induced immunosuppression by inhibiting oxidative stress and mitochondria-mediated apoptosis of mice spleen.


Assuntos
Aflatoxina B1/efeitos adversos , Apoptose/efeitos dos fármacos , Imunossupressão , Licopeno/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Peróxido de Hidrogênio , Interferon gama/sangue , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-2/sangue , Interleucina-2/genética , Interleucina-2/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Baço/lesões , Baço/patologia , Linfócitos T , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
18.
J Appl Microbiol ; 127(3): 856-866, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31161702

RESUMO

AIMS: We developed a strategy for localized delivery of the LFCA (lactoferricinlactoferrampin), which is actively synthesized in situ by Lactococcus lactis (pAMJ399-LFCA/LLMG1363), and explored the possibility of using pAMJ399-LFCA/LLMG1363 as an alternative additive diet to antibiotics. METHODS AND RESULTS: The antimicrobial activities of the LFCA derived from pAMJ399-LFCA/LLMG1363 were tested in vitro. The results showed that LFCA had an inhibitory effect on Staphylococcus aureus, Escherichia coli and Salmonella enteritidis. Then, the pAMJ399-LFCA/LLMG1363 was used as an additive diet for piglets. Our data demonstrated that oral administration of pAMJ399-LFCA/LLMG1363 significantly improved the average daily gain, feed-to-gain ratio, intestinal mucosal integrity and decreased the serum endotoxin and d-lactic acid levels. The mRNA expression levels of intestinal tight junction proteins (including occludin, Claudin-1 and ZO-1) were significantly upregulated by pAMJ399-LFCA/LLMG1363 administration. The serum immunoglobulin G (IgG) levels, intestinal secretory immunoglobulin A (sIgA) levels, IL-2, IL-10 and TGF-ß levels were significantly increased by pAMJ399-LFCA/LLMG1363. Furthermore, our data revealed that oral administration of pAMJ399-LFCA/LLMG1363 significantly increased the number of general Lactobacillus, and decreased the total viable E. coli counts in the ileum and cecum contents. CONCLUSIONS: We developed a novel pAMJ399-LFCA/LLMG1363 secreting LFCA, which had probiotic effects on the growth performance, intestinal morphology, intestinal barrier function and immunological indices of weaned piglets. SIGNIFICANCE AND IMPACT OF THE STUDY: pAMJ399-LFCA/LLMG1363, with probiotic effects on the health of weaned piglets, may be a promising feed additive for weaned piglets.


Assuntos
Antibacterianos/farmacologia , Lactococcus lactis/metabolismo , Lactoferrina/farmacologia , Fragmentos de Peptídeos/farmacologia , Suínos/imunologia , Animais , Bovinos , Escherichia coli/efeitos dos fármacos , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Probióticos/farmacologia , Salmonella enteritidis/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
19.
Carbohydr Polym ; 219: 121-129, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151509

RESUMO

Galectin-3 (Gal-3) can induce T-cell activation and apoptosis and plays a role in tumor immune tolerance. Here, we demonstrate that ginseng pectins selectively inhibit Gal-3-induced T-cell apoptosis, while not affecting T-cell activation. This finding stands in contrast to that from the use of modified citrus pectin (MCP) and potato galactan (P-galactan) that inhibit both. Whereas PKC/ERK and ROS/ERK pathways are involved in both T-cell activation and apoptosis, the Ras/PI3K/Akt pathway is unique to T-cell activation. Ginseng pectins selectively inhibit the ROS/ERK pathway. Using the Sarcomar-180 mouse model in which Gal-3 expression is increased, we found that ginseng pectins (but not MCP or P-galactan) significantly promote T-cell proliferation and IL-2 expression, and inhibit tumor growth by 45%. These in vivo data correlate well with selective effects of pectins on Gal-3-mediated T-cell apoptosis and activation. Our study suggests a novel approach for the development of polysaccharide-based agents that target Gal-3 function.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galactanos/farmacologia , Galectina 3/metabolismo , Panax/metabolismo , Pectinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T , Animais , Linhagem Celular Tumoral , Humanos , Interleucina-2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
20.
Immunohorizons ; 3(2): 71-87, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31236543

RESUMO

We previously reported that neuroimmune semaphorin (Sema) 4A regulates the severity of experimental allergic asthma and increases regulatory T (Treg) cell numbers in vivo; however, the mechanisms of Sema4A action remain unknown. It was also reported that Sema4A controls murine Treg cell function and survival acting through neuropilin 1 (NRP-1) receptor. To clarify Sema4A action on human T cells, we employed T cell lines (HuT78 and HuT102), human PBMCs, and CD4+ T cells in phenotypic and functional assays. We found that HuT78 demonstrated a T effector-like phenotype (CD4+CD25lowFoxp3-), whereas HuT102 expressed a Treg-like phenotype (CD4+CD25hi Foxp3+). Neither cell line expressed NRP-1. HuT102 cells expressed Sema4A counter receptor Plexin B1, whereas HuT78 cells were Sema4A+. All human peripheral blood CD4+ T cells, including Treg cells, expressed PlexinB1 and lacked both NRP-1 and -2. However, NRP-1 and Sema4A were detected on CD3negativeCD4intermediate human monocytes. Culture of HuT cells with soluble Sema4A led to an upregulation of CD25 and Foxp3 markers on HuT102 cells. Addition of Sema4A increased the relative numbers of CD4+CD25+Foxp3+ cells in PBMCs and CD4+ T cells, which were NRP-1negative but PlexinB1+, suggesting the role of this receptor in Treg cell stability. The inclusion of anti-PlexinB1 blocking Ab in cultures before recombinant Sema4A addition significantly decreased Treg cell numbers as compared with cultures with recombinant Sema4A alone. Sema4A was as effective as TGF-ß in inducible Treg cell induction from CD4+CD25depleted cells but did not enhance Treg cell suppressive activity in vitro. These results suggest strategies for the development of new Sema4A-based therapeutic measures to combat allergic inflammatory diseases. ImmunoHorizons, 2019, 3: 71-87.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforinas/metabolismo , Semaforinas/farmacologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Anticorpos , Asma/imunologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Proteínas do Tecido Nervoso/imunologia , Neuropilina-1/metabolismo , Fenótipo , Receptores de Superfície Celular/imunologia , Fator de Crescimento Transformador beta/metabolismo
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